On December 11, 2023 Bristol Myers Squibb (NYSE: BMY) reported updated results from three key programs within its broad multiple myeloma research pipeline, highlighting its diverse targets and molecular approaches to address unique patient needs within the disease (Press release, Bristol-Myers Squibb, DEC 11, 2023, View Source [SID1234638482]). These data were presented at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, California.

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"The data from our multiple myeloma pipeline at ASH (Free ASH Whitepaper) this year continue to demonstrate the progress we are making to deliver the best possible outcomes for patients, leveraging an array of targets matched to the right therapeutic modality based on insights from causal human biology," said Michael Pourdehnad, M.D., senior vice president, Head of Early Clinical Development, Hematology Oncology and Cell Therapy Development, Bristol Myers Squibb. "These programs also represent the strength of our promising pipeline with a growing wave of registrational assets. As we continue to advance these programs, these data provide further evidence of the transformational potential of our cell therapy, protein degradation, and cell engager platforms."

Results being presented at ASH (Free ASH Whitepaper) provide updated evidence for programs including chimeric antigen receptor (CAR) T cell therapies, novel CELMoD agents from our leading protein degradation research platform, and bispecific T cell engagers (TCE):

Updated data from the Phase 1 study of CAR T BMS-986393, a potential first-in-class cell therapy targeting GPRC5D, show deepening responses, a tolerable safety profile, and activity across both B-cell maturation antigen (BCMA)-naïve and -exposed patients (Oral Presentation #219)
New results from the Phase 1 CC-92480-MM-002 study of oral CELMoD agent mezigdomide, including first results for cohorts evaluating mezigdomide and dexamethasone with monoclonal antibodies (anti-CD38 mAbs) daratumumab and elotuzumab (Oral Presentation #1013)
Updated results of the Phase 1 study of alnuctamab, a 2+1 BCMA x CD3 bispecific TCE, show deepening and durable responses, including minimal residual disease (MRD) negativity, along with manageable safety (Poster Presentation #2011)
"Despite continuing advances in care for multiple myeloma, critical unmet needs remain as patients reflect a diverse spectrum of characteristics. Moreover, the disease remains marked by eventual relapse, making the long-term management of the disease paramount," said Joseph Mikhael, M.D., Professor in the Applied Cancer Research and Drug Discovery Division at the Translational Genomics Research Institute and Chief Medical Officer of the International Myeloma Foundation. "Because of this heterogenous profile, having a broad array of options across the treatment path is extremely valuable. Seeing the range of new and updated data being presented at this meeting is encouraging as we look toward the future of myeloma therapy."

GPRC5D CAR T (BMS-986393) Phase 1 Study Results

BMS-986393 is a first-in-class GPRC5D-directed autologous CAR T cell therapy that has the potential to be a best-in-class option for this emerging target.

This Phase 1, first-in-human, multicenter, open-label study is evaluating BMS-986393 in patients with relapsed/refractory multiple myeloma (RRMM) who had received three or more prior lines of therapy. Prior BCMA-targeted treatment, including CAR T cell therapy, was allowed. Primary objectives of the study were to determine safety and tolerability of BMS-986393 and inform the recommended dose for future development.

At the data cutoff of September 11, 2023 (median follow-up of 8.8 months), BMS-986393 continued to demonstrate an efficacy benefit with deep and durable responses in these heavily pretreated patients, including those with prior exposure to BCMA-targeted treatment. The overall response rate (ORR) was 91% (48% complete response rate) among patients treated with the recommended Phase 2 dose (RP2D, n=23), including an ORR of 100% (n=8) in patients with previous exposure to anti-BCMA targeting therapy. Minimal residual disease-negativity was observed in 86% (n=14) of evaluable patients.

BMS-986393 demonstrated a well-tolerated safety profile, and the RP2D was declared as 150 x 106 CAR T cells without reaching the maximum tolerated dose. The benefit-risk profile remained consistent with earlier, previously presented data cuts. Overall, most patients regardless of treatment dose experienced a treatment emergent adverse event (n=84; any Grade: 91.7%, Grade 3/4: 82.1%). Cytokine release syndrome (CRS) was common with the majority of events being manageable and low grade (any Grade: 76.2%, Grade 3/4: 3.6%) including in patients treated at RP2D where all CRS events were Grade 1 (88.5%). ICANS-type neurotoxicity events were not common across all dose levels (any Grade: 9.5%, Grade 3: 2.4%) and were reversible with or without intervention; among patients treated at RP2D all ICANS events were low grade (any Grade: 3.8%, Grade 3/4: 0%). The incidence of non-ICANS neurotoxicity was similar for patients treated at RP2D as compared with all patients (15.4% vs. 10.7%, respectively). On-target/off-tumor skin, nail, and oral adverse events (AEs) were all low-grade, transient, and the majority (86%) did not require treatment.

These early clinical data suggest a single infusion of BMS-986393 is tolerable and efficacious in RRMM, including in those with prior exposure to BCMA-targeted therapy​, and a single-arm Phase 2 trial of BMS-986393 in patients with RRMM exposed to four or more classes of therapy (quadruple-class exposed) is planned to open in the first half of 2024.

Novel oral CELMoD agent mezigdomide Phase 1/2 Study Results

Cereblon E3 ligase modulators (CELMoDs), representing one of three modalities from the company’s leading protein degradation platform, are a class of oral therapeutics that are optimized to both stimulate the immune system and directly kill cancer cells by inducing the degradation of tumor-promoting proteins. The CELMoD agents, mezigdomide and iberdomide, are adaptable combination and sequencing partners being investigated in multiple myeloma.

The mezigdomide CC-92480-MM-002 trial is an ongoing open-label, international Phase 1/2 study evaluating the safety and efficacy of mezigdomide with different treatment combinations in patients with RRMM. At ASH (Free ASH Whitepaper), first results were presented for combinations of mezigdomide and dexamethasone plus monoclonal antibodies (anti-CD38 mAbs) elotuzumab (MeziEd, Cohort H=21/28 days) or one of three dosing schedules of daratumumab (MeziDd, Cohort B1= 21/28 days, Cohort B2=14/21 days, Cohort B3=7/14 days x2). Patients had a median of 3 (range 2-5) prior therapies including stem cell transplantation, proteasome inhibitors, anti-CD38 agents or IMiD agents. The primary objectives of the study were to determine the RP2D, safety, and preliminary overall response rate (ORR).

Results at ASH (Free ASH Whitepaper) showed mezigdomide combined with anti-CD38 mAbs showed encouraging efficacy in previously treated patients. Patients treated with MeziDd achieved a response regardless of dose and schedule, with ORR observed in 82.6% of patients in Cohort B1 (n=23), 62.1% of patients in Cohort B2 (n=18) and 88.9% of patients in Cohort B3 (n=18). MeziEd was active in patients who were refractory to prior anti-CD38 mAb therapy, with an ORR of 45% in Cohort H (n=20). MeziDd and MeziEd were pharmacodynamically active at all schedules and dose levels tested. Further investigation is underway to determine the optimal dose and schedule for MeziDd based on Cohort B3.

The safety profile of mezigdomide in combination with anti-CD38 mAbs was manageable and consistent with prior reports. Most Grade 3/4 treatment-emergent adverse events (TEAEs) following treatment with MeziDd or MeziEd were hematologic, with neutropenia being the most common and ranging from 40-70% across cohorts. The occurrence of Grade 3/4 non-hematologic TEAEs was relatively low with either combination.

Mezigdomide is currently being evaluated in two randomized pivotal Phase 3 studies, including SUCCESSOR-1 (NCT05519085: mezigdomide, bortezomib and dexamethasone vs. pomalidomide, bortezomib and dexamethasone in patients with lenalidomide-exposed RRMM) and SUCCESSOR-2 (NCT05552976: mezigdomide with carfilzomib and dexamethasone vs. carfilzomib and dexamethasone in patients with anti-CD38 and lenalidomide exposed RRMM).

Alnuctamab (BMS-986349/CC -93269) Phase 1 Study Results

Alnuctamab is a bispecific T cell engager (TCE) that simultaneously binds myeloma cells expressing BCMA and T cells (via CD3) in a unique 2:1 fashion. This interaction aims to drive myeloma cell death by inducing T cell activation and release of proinflammatory cytokines and cytolytic enzymes.

In the ongoing alnuctamab CC-93269-MM-001 open-label, Phase 1 study, 78 patients with RRMM were treated with subcutaneous (SC) alnuctamab in two step-up doses (3 mg and 6 mg) followed by escalating target doses of 10, 15, 30, and 60 mg, given every one week for three months, then every two weeks for three months, followed by every four weeks after those six months.

In updated results, SC alnuctamab showed durable responses with high anti-tumor activity observed at target dose of 30 mg (n=32), the dose selected for Phase 3. In the efficacy-evaluable patients treated with SC alnuctamab (n=73), the ORR was 53% across all doses and 67% at the 30 mg target dose. Median time to response was 1.2 months (range, 0.9–4.0) and responses deepened over time. Median progression-free survival (PFS) was 10.1 months (95% CI, 2.8–17.8) across all dose levels and 11.4 months (95% CI, 1.8 to not estimable) in the 30 mg target dose. Median duration of response (DOR) had not been reached at the time of data cutoff. All patients who achieved a response at the 30 mg target dose (14/14) were MRD-negative.

The safety profile was manageable and no Grade 3/4 CRS was observed. The most common Grade 3 or higher hematologic TEAEs across target doses (n=78) were neutropenia (46%), anemia (26%) and thrombocytopenia (17%) with the most common non-hematologic Grade 3 or higher TEAE being infections (17%).

A Phase 3 study of alnuctamab in patients with RRMM exposed to lenalidomide and an anti-CD38 monoclonal antibody is planned and will be initiated in the first half of 2024.